Natural killer receptor-mediated regulation of dendritic cell functions in chronic hepatitis C

天然杀伤（NK）细胞是专门的淋巴细胞，通过其杀死病原体感染细胞和转化细胞的能力提供第一道防线。NK细胞的功能受抑制和激活信号的精细平衡调节，这些信号由多种细胞表面受体介导。我们最近发现慢性丙型肝炎患者NK细胞上抑制性受体CD 94/NKG 2A的表达上调。HLA-E是NKG 2A的配体，在所有检测的人肝癌细胞系以及非转化肝细胞中表达，但在经典的NK敏感性靶细胞K562细胞中不表达。从慢性丙型肝炎患者中分离的NK细胞（HCV-NK）对肝癌细胞的杀伤能力和对肝癌细胞产生IFNγ的能力低于健康供体，而对K562细胞的NK反应性无显著差异。值得注意的是，发现在HCV-NK和肝癌细胞存在下，单核细胞衍生的树突状细胞的成熟和活化受到负调节，这通过在HCV-NK和肝癌细胞共培养期间添加抗NKG 2A抗体而恢复。研究表明，树突状细胞通过Toll样受体监测病原体相关的分子模式来识别来自微生物的危险信号。我们的发现揭示了NK受体作为一个重要的界面，将危险信号从异常细胞传递到免疫系统。CD 94/NKG 2A的异常表达可能对慢性丙型肝炎患者的先天性抵抗和随后的针对HCV感染或转化细胞的适应性免疫产生负面影响。

Natural kilier (NK) cells are specialized lymphocytes that provide a first line of defense through their ability to kill pathogen-infected cells and transformed cells. The function of NK cells is regulated by a fine balance of inhibitory and activating signals, which are mediated by a diverse array of cell-surface receptors. We recently found that expression of the inhibitory receptor CD94/NKG2A is upregulated on NK cells in patients with chronic hapatitis C. HLA-E, a ligand for NKG2A, was expressed in all human hepatoma cell lines tested as well as non-transformed hepatocytes, but not in K562 cells, a classical NK-sensitive target. NK cells isolated from patients with chronic hepatitis C (HCV-NK) were less capable of killing hepatoma cells and of producing IFNγ in response to hepatoma cells than those from healthy donors, whereas there was no significant difference in NK responsiveness towards K562 cells. Of note is the finding that maturation and activation of monocyte-derived dendritic cells were negatively modulated in the presence of HCV-NK and hepatoma cells, which was restored by the addition of anti-NKG2A antibody during the coculture of HCV-NK and hepatoma cells. Research revealed that dendritic cells recognize danger signals from microorganisms by monitoring pathogen-associated molecular patterns via Toll-like receptors. Our findings have shed light on NK receptors as an important interface that transmits danger signals from abnormal cells to immune systems. Aberrant expression of CD94/NKG2A should have negative impact on innate resistance and subsequent adaptive immunity towards HCV-infected or transformed cells in chronic hepatitis C.